Asthma is an increasingly common disease caused by bronchial inflammation and characterized by bronchial hyperresponsiveness and intermittent airways obstruction. The development of asthma is most likely determined by an interaction between host susceptibility and environmental exposures. Bronchial hyperresponsiveness (BHR) and elevated total serum IgE levels, characteristic findings in asthma, have been shown to have strong genetic components. The identification of the genetic factors that regulate susceptibility to asthma has important public health consequences, and may lead to an improved understanding of the pathogenesis of asthma. This may lead to improved preventive measures and new therapeutic approaches. In an effort to delineate genetic susceptibility to asthma, we have identified several regions of the genome that contain potential asthma susceptibility genes using a Dutch population of 200 families ascertained through a proband with asthma. The two regions with the strongest evidence for linkage after completing a genome screen were located on chromosomes 3p14-p21 and 5q3l. The goal of this proposal is to identify the asthma susceptibility gene located on chromosome 3p using the Dutch families and determine its contribution to this disease in other populations. The aims of this proposal are: 1) Develop a high-resolution genetic map of the candidate region on chromosome 3pl4-p21. 2) Construct a correlated genetic and physical map of the candidate region on chromosome 3p. 3) Genotype an additional cohort of Dutch trios (one affected child and both parents) to identify haplotypes and to confirm case-control candidate gene studies. 4) Analyze known and novel genes from the candidate region using a case-control study design in the same population. 5) Determine the contribution of the chromosome 3p asthma susceptibility gene in other populations including the U.S. Collaborative Study for the Genetics of Asthma (CSGA) and Dr. Ober's Hutterite population. 6) Characterize the identified SNP or haplotype that contributes to asthma susceptibility. As part of this project, it will be very important to interact with other funded investigators to determine the impact of each genetic locus and to investigate gene-gene interactions.